Benjamin P. Levy, MD: Let’s finish off with a brief discussion on combination strategies in the ALK space. We talk a lot about immunotherapy in the EGFR space, and the efficacy, or lack thereof. Are there data, or should we be looking at immunotherapy in the ALK space? We have some fairly consistent data. For single-agent immunotherapy in ALK-rearranged lung cancer, the response rate is around 0%. That’s not hyperbole. We have combination strategies that we’re looking at, looking at ALK tyrosine kinase inhibitors with immunotherapy. Is there a role for that, Jonathan? Do we think that’s something that can move forward?

Jonathan W. Riess, MD, MS: Combining ALK inhibitors with immunotherapy has been tested in a few studies. There was one recently presented at the 2018 ASCO Annual Meeting. It looked at a phase Ib study of alectinib and atezolizumab in ALK-positive non–small cell lung cancer. It enrolled 21 patients in the treatment-naïve setting. Essentially, they found results that were, in terms of efficacy, comparable to alectinib alone: an overall response rate of 81% and a median progression-free survival of 21.7 months. If anything, although small numbers, it’s a bit less than what was observed in the ALEX trial data that was updated this year.

There was a 62% rate of grade 3 and serious adverse events. So, I would not recommend immunotherapy with ALK TKI therapy as a combination strategy. In terms of other combination strategies, there are some trials looking at VEGF inhibition, for example, with bevacizumab and alectinib. There are some other trials that are ongoing that are looking at other inhibitors in combination with ALK TKIs. I think that those strategies, as well as the newer-generation ALK TKIs, appear to have more legs than combining immunotherapy with an ALK TKI.

Benjamin P. Levy, MD: Yes. I think we’ve got a lot of work to do. We certainly have a lot of combinations that are rooted in scientific rationale, but we need to iron them out clinically to see what sticks. Before we move on to the next section, let’s briefly comment on ROS. It’s another approved biomarker. What is your experience with ROS and the drugs that are approved in ROS-rearranged lung cancer?

Alexander Drilon, MD: That’s a pretty easy question to answer. There’s only 1 treatment. Interestingly, it’s crizotinib. In addition to being an ALK and MET inhibitor, it is a ROS-1 inhibitor. Response rates exceed 60%. But, very interestingly, compared with ALK, the duration of disease control seems to be longer. You’re seeing almost more than double what you expect to see, in terms of meeting progression-free survival. There are other drugs that are being investigated—entrectinib, for example. There is also some preclinical activity with lorlatinib, and we hope that we hear more about that and other drugs in the future. Hopefully, we’ll see some type of sequential therapy for ROS-1 emerge, similar to ALK and EGFR.

Zofia Piotrowska, MD: One thing that I think is sometimes a little confusing is we often lump ALK and ROS-1 together. For some drugs, like for crizotinib or lorlatinib, that may be appropriate, but not all of the ALK inhibitors seem to have good ROS-1 activity. We know, for example, that alectinib really doesn’t have very good activity against ROS-1. I don’t know about brigatinib.

Alexander Drilon, MD: There’s also a Korean ceritinib study that was presented that shows activity.

Benjamin P. Levy, MD: There is a lot to keep up with here.

Transcript Edited for Clarity

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Transcript:

Benjamin P. Levy, MD: Let’s finish off with a brief discussion on combination strategies in the ALK space. We talk a lot about immunotherapy in the EGFR space, and the efficacy, or lack thereof. Are there data, or should we be looking at immunotherapy in the ALK space? We have some fairly consistent data. For single-agent immunotherapy in ALK-rearranged lung cancer, the response rate is around 0%. That’s not hyperbole. We have combination strategies that we’re looking at, looking at ALK tyrosine kinase inhibitors with immunotherapy. Is there a role for that, Jonathan? Do we think that’s something that can move forward?

Jonathan W. Riess, MD, MS: Combining ALK inhibitors with immunotherapy has been tested in a few studies. There was one recently presented at the 2018 ASCO Annual Meeting. It looked at a phase Ib study of alectinib and atezolizumab in ALK-positive non–small cell lung cancer. It enrolled 21 patients in the treatment-naïve setting. Essentially, they found results that were, in terms of efficacy, comparable to alectinib alone: an overall response rate of 81% and a median progression-free survival of 21.7 months. If anything, although small numbers, it’s a bit less than what was observed in the ALEX trial data that was updated this year.

There was a 62% rate of grade 3 and serious adverse events. So, I would not recommend immunotherapy with ALK TKI therapy as a combination strategy. In terms of other combination strategies, there are some trials looking at VEGF inhibition, for example, with bevacizumab and alectinib. There are some other trials that are ongoing that are looking at other inhibitors in combination with ALK TKIs. I think that those strategies, as well as the newer-generation ALK TKIs, appear to have more legs than combining immunotherapy with an ALK TKI.

Benjamin P. Levy, MD: Yes. I think we’ve got a lot of work to do. We certainly have a lot of combinations that are rooted in scientific rationale, but we need to iron them out clinically to see what sticks. Before we move on to the next section, let’s briefly comment on ROS. It’s another approved biomarker. What is your experience with ROS and the drugs that are approved in ROS-rearranged lung cancer?

Alexander Drilon, MD: That’s a pretty easy question to answer. There’s only 1 treatment. Interestingly, it’s crizotinib. In addition to being an ALK and MET inhibitor, it is a ROS-1 inhibitor. Response rates exceed 60%. But, very interestingly, compared with ALK, the duration of disease control seems to be longer. You’re seeing almost more than double what you expect to see, in terms of meeting progression-free survival. There are other drugs that are being investigated—entrectinib, for example. There is also some preclinical activity with lorlatinib, and we hope that we hear more about that and other drugs in the future. Hopefully, we’ll see some type of sequential therapy for ROS-1 emerge, similar to ALK and EGFR.

Zofia Piotrowska, MD: One thing that I think is sometimes a little confusing is we often lump ALK and ROS-1 together. For some drugs, like for crizotinib or lorlatinib, that may be appropriate, but not all of the ALK inhibitors seem to have good ROS-1 activity. We know, for example, that alectinib really doesn’t have very good activity against ROS-1. I don’t know about brigatinib.